1. Field of Invention
This invention relates to the preparation and sterilization of povidone-iodine ointment used for topical disinfection, and more specifically, to the ingredients in the ointment mixture, their relative weight percentages with respect to one another, and how the ingredients are combined into a mixture are also a part of this invention.
2. Background Description
Ointments are recognized as salves or unguents for application to the skin as a semi-solid medicinal preparation. The idea of an ointment is to have a soft unctuous preparation which at room temperature exists as primarily a separate soft free standing solid that does not flow. The ointment should have a wet or moist looking surface appearance with no visible separation of the solid and wet portions.
Povidone-iodine ointments used in the topical antimicrobial treatment of human and animal skin are formulated with povidone-iodine (a complex of povidone and iodine) and contain sufficient iodine in active form to kill microbes. Consequently, povidone-iodine treats wounds and skin abrasions. Topical disinfection solutions containing povidone-iodine are used as cleansing and patient pre-operative preparing agents and are well recognized as a germicidal agent which is safe, non-irritating to the skin and shelf stable for a commercially acceptable period of time. Povidone-iodine powder has been used in making iodophor ointments for topical disinfection.
Polyvinylpyrrolidone is a homo-polymer of 1-ethenyl-2-pyrrolidinone also known as 1 vinyl-2-pyrrolidinone polymer. A common name for this chemical substance is povidone and the compound is sometimes designated as PVP. Povidone is a synthetic polymer having linear 1-vinyl-2-pyrrolidinone groups polymerized into polymer chains of various molecular weights, generally having mean molecular weights ranging from about 10,000 to 700,000. Polymers of both lesser and higher molecular weights are known.
Povidone is available as, either as a dry powder or in aqueous solution for use in a wide variety of chemical, pharmaceutical and food manufacturing processes as well as special industrial compositions such as inks, paints and emulsions, cosmetics and germicidal products. Povidone, in manufacture and formulation of different compositions, contributes to the viscosity of the fluid medium being used. The viscosity contribution of povidone ranges from higher to low viscosity as a function of the average molecular weight of the polymer. Povidone is classified by K-values which are assigned to the various povidone polymers, the smaller the K-value, the lower the intrinsic viscosity of the polymer solution.
The more common commercially available povidone polymers have K-values of K-17, K-30, K-60 and K-90. In aqueous solutions, povidone K-17 and povidone K-30 have little effect on viscosity in concentrations below 10%, whereas povidone K-60 and povidone K-90 have considerable influence on the flow properties of a solution at such concentrations. Moreover, certain organic solvents have a particular effect on the viscosity contribution of povidone, the intensity of which is related to the polarity of the particular organic solvent.
Cross-linkage of the povidone polymer is influenced by diverse factors as for example, actinic light, diazo compounds, oxidizing agents and heat. Cross-linking of the povidone polymer is a serious limitation to its use since the povidone polymer is altered into an aqueous insoluble form. The presence of certain substances in the povidone solution will accelerate cross-linking at even lower temperatures. When a povidone solution is heated to 100.degree. C., in the alkaline pH range, the polymer becomes permanently altered to be irreversibly insoluble. Similar cross-linked changes occur when alkaline sodium phosphate buffers are used and when an oxidizing agent such as ammonium persulfate is added to a povidone solution, cross-linking gel formation occurs in about 30 minutes when the combination is heated at moderate temperatures of about 90.degree. C.
Therefore, aqueous solutions of povidone subjected to autoclaving to sterilize povidone preparations, may cause degradation of the polymer. Thus for example, povidone which is stable to moderate heat will darken in color and decrease in water solubility when heated to about 150.degree. C. The cross-linking of the polymer caused by heat, oxidizing agents, salts and other substances presents special problems in the manufacture and processing of certain compositions containing povidone, when these povidone solutions are intended for parenteral use, since the formed insoluble cross-linked povidone may initiate thrombotic episodes and other noxious events. When povidone is used in the manufacture of those preparations requiring sterilization but containing oxidizing agents or other oxygen sources, then similar incompatibility occurs to limit the use of povidone in the preparations.
For medical products gamma radiation, an effective sterilizing process, is notoriously unsuited for use with povidone polymers. The particular degradative effects followed by cross-linkage and gelation occurring when povidone is exposed to even minimal gamma radiation dosage is well known. The formation of a stable ointment to be subject to gamma radiation is of concern. The actions of radiation on povidone, together with radiolysis products formed in the composition, results in macroradical polymer chain formation and these macroradicals further inter-react so that the ultimate effect of radiation is either cross-linkage gelation or chain scission.
When povidone solutions are irradiated with gamma radiation, gelation occurs when the concentration of povidone in solution is above 0.3% to 1% by weight of povidone. For the lower molecular weight of K-30 and below concentrations between 0.3% and 0.5% are acceptable. Below this critical concentration limit, macrogelation to form a wall-to-wall gel, is not readily observed.
The sensitivity of povidone to low dosages of gamma radiation is so pronounced that adverse gelation crosslinkage effects are observed after irradiation with doses as low as 0.1 kilorad, when the noted concentration of povidone in solution is exceeded. The use of povidone in most industrial, agricultural and pharmaceutical manufacturing procedures exceeds the concentration limits established for the gamma radiation of povidone. The concentration level for povidone is further adversely modified by ionizing solutions, and pH. This destructive, degradative response of povidone to gamma radiation which destroys its desirable properties in the formulation precludes the use of gamma radiation as a means to render povidone and povidone-containing compositions free of microbial contamination.
Thus, attempts to produce sterilized povidone-iodine by irradiation of the povidone prior to formulation of the povidone-iodine are complicated by the described problems of gamma radiation of the povidone. The sterilization of povidone-iodine after formation is found to be unsatisfactory because the irradiation has the effect of decreasing the amount of available iodine with consequent reduction in antibacterial activity. Commercially available povidone-iodine ointments typically thickened by using cellulosic fillers which upon irradiation undergo severe degradation turning into liquids with a water like consistency.
A povidone-iodine ointment which is easy to mix and sterilize without loss of viscosity or antimicrobial activity has not been available. The ability to gamma radiate to sterilize the mixture without viscosity changes to the desired free standing ointment and without significant loss of available iodine or reduction in antibacterial activity over a reasonable shelf life time period is unknown.